PROJECT SUMMARY/ABSTRACT With no approved medications for methamphetamine (MA) use disorder, a major public health problem, new treatment approaches are needed. Striatal dopamine D2-type receptor (DRD2/3) availability (binding potential, BPND) is linked to indices of cognitive control, and MA users show deficits in both. Striatal DRD2/3 BPND release can predict outcomes of behavioral treatments for stimulant dependence. Thus, DRD2/3 signaling is a logical therapeutic target, but dopamine agonists have not been successful treatments, perhaps due to underlying pathology involving DRD2/3. We suggest that promoting dopaminergic neuroplasticity may ameliorate neurobehavioral problems associated with MA use disorder. Our preliminary data indicate that adding an exercise program can increase striatal DRD2/3 BPND in MA users receiving behavioral treatment. If such an increase can improve neurocognitive function, it may be a useful therapeutic adjunct for stimulant use disorders. We have shown that in healthy control subjects, striatal DRD2/3 BPND is linked with performance and neural activity related to self-control and cognitive flexibility. To determine whether exercise can improve function in these and other cognitive domains, we will randomize individuals with MA use disorder (males and females, 18-45 years) in a residential behavioral treatment program to two groups: 1) Exercise-Group participants will be in an 8-week, moderate-intensity exercise training program; 2) Control-Group participants will be in parallel health-education sessions with equal time and supervision. We will assess DRD2/3 BPND with PET, and neural activity in tests of inhibitory control and cognitive flexibility during fMRI. We have four specific aims: 1) confirm that adding exercise to behavioral treatment produces striatal DRD2/3 upregulation in MA users; 2) compare effects of the exercise and control conditions on performance and associated neural activity during tests of inhibitory control and cognitive flexibility, and on performance in a cognitive battery; 3) test whether effects on cognitive control and brain function are related to changes in DRD2/3 BPND; and 4) compare the effects of the exercise and control conditions on simulated MA choice and actual MA use. We expect that: 1) BPND will increase more in the exercise condition than the control condition; 2) the exercise group will show more improvement than the controls in task performance and activation within executive-control regions during fMRI, and in performance on a cognitive test battery; 3) DRD2/3 BPND increases in exercise-group participants will be positively associated with changes in task performance and neural activity; and 4) both virtual MA choice, measured in the laboratory, and MA use, measured by self-report and urine tests at follow-up, will be lower in participants in the exercise group and will be negatively related to DRD2/3 BPND at the end of the intervention. The use of exercise training as a way to alter brain chemistry and function in individuals with MA use disorder is a novel approach with the potential to provide mechanistic information that ultimately may help inform treatment.